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Effect of Salbutamol on Walking Capacity in Ambulatory ALS Patients (WALKALS)

Primary Purpose

Walking Capacity, Amyotrophic Lateral Sclerosis

Status
Not yet recruiting
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Salbutamol
Placebo
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Walking Capacity focused on measuring Amyotrophic Lateral Sclerosis, Walking capacity, Salbutamol, Ventolin

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Subjects who meet the revised El Escorial criteria for probable or definite sporadic ALS Adult patients between 18 and 75 years of age Patients who are ambulatory and able to perform the 6MWT and quantitative muscle testing at screening (ALSFRS-R-walking = 3) Patients able and willing to travel to the site, and, in the investigator's opinion, who are likely to attend visits for at least 6 months Patients who signed written informed consent Stable dose of riluzole for a minimum of 4 weeks prior to baseline or has not taken it for 4 weeks prior to baseline For child-bearing aged women, efficient contraception (cf protocol p32) Forced vital capacity (fVC) in a sitting position > 70 % Exclusion Criteria: Patients with significant spasticity of the lower limbs interfering with walking capacity (Ashworth scale score > 2) Patients with fronto-temporal dementia associated with ALS Patients presenting respiratory insufficiency causing dyspnea during walking Patients taking drugs that could interfere with NMJ function (anticholinesterase …) or muscle function (steroids, statins…) Patients taking any forbidden drugs (see list in annex) Hypersensitivity to salbutamol or to excipients of the drug and placebo Known contraindication for the studied drug such as ischemic cardiomyopathy or risk of ischemic cardiomyopathy: history of ischemic heart disease or coronaropathy or/and significant ischemic ECG alterations at screening visit Any clinically significant alterations in the following biological parameters glycemia, kalemia, creatinemia and hematology in the month prior to inclusion according to local laboratory threshold (cf protocol page 33) Vulnerable persons defined in Articles L1121-5 to L 1121-8-1 and L1122-1-2 of the Code de la Santé Publique* (*CSP) Participation in another interventional trial up to 3 months before inclusion Patients having any relevant concomitant disease considered at risk of interfering with study procedures in the opinion of the investigator

Sites / Locations

  • Hôpital Pitié Salpêtrière

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Salbutamol

placebo of salbutamol

Arm Description

Salbutamol 2mg/5ml syrup : 2mg TID salbutamol for 3 months, then 4 mg TID for 3 months For each investigated dose (6 mg then 12 mg), the treatment will be titrated during a 4 days period: At beginning of the first 3-month period : Month 0 D1: 2mg in the morning; D2-D3: 2 mg in the morning and 2mg in the evening for two days; From D4 and until the end of first 3-month period (until the M3 follow-up visit): 2mg in the morning, at noon and in the evening At beginning of the second 3-month period : Month 3 D1: 4mg in the morning, 2mg at noon, 2 mg in the evening; D2: 4 mg in the morning, 2 mg at noon and 4mg in the evening; J4 and for 3 months (until the M6 follow-up visit) : 4mg in the morning, at noon and in the evening.

Placebo syrup : 2mg TID salbutamol for 3 months, then 4 mg TID for 3 months For each investigated dose (6 mg then 12 mg), the treatment will be titrated during a 4 days period: At beginning of the first 3-month period : Month 0 D1: 2mg in the morning; D2-D3: 2 mg in the morning and 2mg in the evening for two days; From D4 and until the end of first 3-month period (until the M3 follow-up visit): 2mg in the morning, at noon and in the evening At beginning of the second 3-month period : Month 3 D1: 4mg in the morning, 2mg at noon, 2 mg in the evening; D2: 4 mg in the morning, 2 mg at noon and 4mg in the evening; J4 and for 3 months (until the M6 follow-up visit) : 4mg in the morning, at noon and in the evening.

Outcomes

Primary Outcome Measures

walking capacity
6 minutes walking test distance (6MWT)
walking capacity
6 minutes walking test distance (6MWT)

Secondary Outcome Measures

Target engagement:
percentage of change of the decrement at electromyography after repetitive nerve stimulation.
functional quantitative decline description over time in ALS patients
Revised ALS Functional Rating Scale-r (ALSFRS-r) composed by 12 questions scoring from 0 to 4 with a maximal score of 48
walking scale
Twelve items Multiple Sclerosis (MS) Walking Scale (12-MSWS) ( score: 5 to 60 ( severe difficulty)) . Walking improvement on the MSWS-12 is indicated by negative change scores.
Fatigue and depression scale
Fatigue Severity Scale (FSS) is a 9-item scale which measures the severity of fatigue and its effect on a person's activities and lifestyle in patients with a variety of disorders. ( score : 9 (no fatigue ) to 63 (extreme fatigue)
Respiratory assessment
Forced Vital Capacity (FVC): the maximum amount of air that a person can exhale as hard and as long as possible from the lungs after a maximum inspiration and Forced Expiratory Volume in the first second of exhalation (FEV1) : FEV1 is the most frequently used index for assessing airway obstruction, bronchoconstriction or bronchodilation
Thigh muscle volume
bioelectrical impedance analysis (BIA)
Muscle volume
Muscle MRI in cm3
Biomarkers of muscle damage
CPK, LDH and creatinine serum levels
Quality of life scale
The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) ( score: 0 to 160 bad quality of life)
Motor unit number
Motor unit count (MUNIX method)

Full Information

First Posted
April 24, 2023
Last Updated
May 5, 2023
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT05860244
Brief Title
Effect of Salbutamol on Walking Capacity in Ambulatory ALS Patients
Acronym
WALKALS
Official Title
Effect of Salbutamol on Walking Capacity in Ambulatory ALS Patients
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
June 2023 (Anticipated)
Primary Completion Date
July 2025 (Anticipated)
Study Completion Date
July 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Preclinical and clinical data strongly suggest that administration of salbutamol in ALS patients may improve walking capacity related to motor fatigue by enhancing neuromuscular transmission. Salbutamol may exert a neuroprotective effect and slow down the progression of clinical signs and symptoms. The main objective of the study is to test the efficacy of salbutamol on walking capacity in ALS patients and the secondary objective is to measure the target engagement of salbutamol on the neuromuscular junction (NMJ) at EMG (decrement of repetitive nerve stimulation in three nerves/muscle couples), as well as safety and tolerability. The exploratory objectives are to study the effect of salbutamol on fatigue scales, muscle strength, respiratory function, motor unit count, muscle and spinal MRI parameters and blood biomarkers
Detailed Description
Based on a strong preclinical and clinical rationale the main hypothesis is that the administration of salbutamol in ALS patients may improve the walking capacity related to motor fatigue by enhancing the neuromuscular transmission. Salbutamol may also exert a neuroprotective effect and slow down the progression of clinical signs and symptoms. To test these hypotheses, the investigator team will implement a monocentric, randomized, controlled, pilot study to evaluate the effect of salbutamol on walking capacity in ambulatory ALS patients with a total duration of 24 months and a treatment period of 6 months for each patient. The project Team will use as secondary and exploratory endpoints target engagement and efficacy up-to date biomarkers such as quantitative muscle strength evaluation, functional neuromuscular evaluation and spinal and muscle MRI. Tolerability and safety will also be studied. Salbutamol has been used for a long time and is usually well tolerated. The objective of the study is to evidence a signal of efficacy paving the way for a confirmatory phase 3 trial. In parallel to this, the use of muscle and spinal MRI as well as of quantitative muscle strength evaluation as exploratory endpoints will pave the way to their development as biomarkers of disease progression in ALS. Thanks to the data collected in this study, the team will give proof of their accuracy, with a view to ameliorate the prognostication and monitoring of disease progression and survival, as well as to improve the understanding of the interaction between muscular and central degeneration. A further aim of this study will be to provide a proof of concept that spinal and muscle MRI can constitute a biomarker of the efficacy of investigational drugs targeting muscles.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Walking Capacity, Amyotrophic Lateral Sclerosis
Keywords
Amyotrophic Lateral Sclerosis, Walking capacity, Salbutamol, Ventolin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Salbutamol
Arm Type
Experimental
Arm Description
Salbutamol 2mg/5ml syrup : 2mg TID salbutamol for 3 months, then 4 mg TID for 3 months For each investigated dose (6 mg then 12 mg), the treatment will be titrated during a 4 days period: At beginning of the first 3-month period : Month 0 D1: 2mg in the morning; D2-D3: 2 mg in the morning and 2mg in the evening for two days; From D4 and until the end of first 3-month period (until the M3 follow-up visit): 2mg in the morning, at noon and in the evening At beginning of the second 3-month period : Month 3 D1: 4mg in the morning, 2mg at noon, 2 mg in the evening; D2: 4 mg in the morning, 2 mg at noon and 4mg in the evening; J4 and for 3 months (until the M6 follow-up visit) : 4mg in the morning, at noon and in the evening.
Arm Title
placebo of salbutamol
Arm Type
Placebo Comparator
Arm Description
Placebo syrup : 2mg TID salbutamol for 3 months, then 4 mg TID for 3 months For each investigated dose (6 mg then 12 mg), the treatment will be titrated during a 4 days period: At beginning of the first 3-month period : Month 0 D1: 2mg in the morning; D2-D3: 2 mg in the morning and 2mg in the evening for two days; From D4 and until the end of first 3-month period (until the M3 follow-up visit): 2mg in the morning, at noon and in the evening At beginning of the second 3-month period : Month 3 D1: 4mg in the morning, 2mg at noon, 2 mg in the evening; D2: 4 mg in the morning, 2 mg at noon and 4mg in the evening; J4 and for 3 months (until the M6 follow-up visit) : 4mg in the morning, at noon and in the evening.
Intervention Type
Drug
Intervention Name(s)
Salbutamol
Intervention Description
Salbutamol for 6 months
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo Syrup for 6 months
Primary Outcome Measure Information:
Title
walking capacity
Description
6 minutes walking test distance (6MWT)
Time Frame
Month 6
Title
walking capacity
Description
6 minutes walking test distance (6MWT)
Time Frame
Month 3
Secondary Outcome Measure Information:
Title
Target engagement:
Description
percentage of change of the decrement at electromyography after repetitive nerve stimulation.
Time Frame
baseline, month 3, month 6
Title
functional quantitative decline description over time in ALS patients
Description
Revised ALS Functional Rating Scale-r (ALSFRS-r) composed by 12 questions scoring from 0 to 4 with a maximal score of 48
Time Frame
baseline, month 3, month 6
Title
walking scale
Description
Twelve items Multiple Sclerosis (MS) Walking Scale (12-MSWS) ( score: 5 to 60 ( severe difficulty)) . Walking improvement on the MSWS-12 is indicated by negative change scores.
Time Frame
baseline, month 3, month 6
Title
Fatigue and depression scale
Description
Fatigue Severity Scale (FSS) is a 9-item scale which measures the severity of fatigue and its effect on a person's activities and lifestyle in patients with a variety of disorders. ( score : 9 (no fatigue ) to 63 (extreme fatigue)
Time Frame
baseline, month 3, month 6
Title
Respiratory assessment
Description
Forced Vital Capacity (FVC): the maximum amount of air that a person can exhale as hard and as long as possible from the lungs after a maximum inspiration and Forced Expiratory Volume in the first second of exhalation (FEV1) : FEV1 is the most frequently used index for assessing airway obstruction, bronchoconstriction or bronchodilation
Time Frame
baseline, month 3, month 6
Title
Thigh muscle volume
Description
bioelectrical impedance analysis (BIA)
Time Frame
baseline, month 3, month 6
Title
Muscle volume
Description
Muscle MRI in cm3
Time Frame
baseline, month 3, month 6
Title
Biomarkers of muscle damage
Description
CPK, LDH and creatinine serum levels
Time Frame
baseline, month 3, month 6
Title
Quality of life scale
Description
The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) ( score: 0 to 160 bad quality of life)
Time Frame
baseline, month 6
Title
Motor unit number
Description
Motor unit count (MUNIX method)
Time Frame
baseline, month 6

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subjects who meet the revised El Escorial criteria for probable or definite sporadic ALS Adult patients between 18 and 75 years of age Patients who are ambulatory and able to perform the 6MWT and quantitative muscle testing at screening (ALSFRS-R-walking = 3) Patients able and willing to travel to the site, and, in the investigator's opinion, who are likely to attend visits for at least 6 months Patients who signed written informed consent Stable dose of riluzole for a minimum of 4 weeks prior to baseline or has not taken it for 4 weeks prior to baseline For child-bearing aged women, efficient contraception (cf protocol p32) Forced vital capacity (fVC) in a sitting position > 70 % Exclusion Criteria: Patients with significant spasticity of the lower limbs interfering with walking capacity (Ashworth scale score > 2) Patients with fronto-temporal dementia associated with ALS Patients presenting respiratory insufficiency causing dyspnea during walking Patients taking drugs that could interfere with NMJ function (anticholinesterase …) or muscle function (steroids, statins…) Patients taking any forbidden drugs (see list in annex) Hypersensitivity to salbutamol or to excipients of the drug and placebo Known contraindication for the studied drug such as ischemic cardiomyopathy or risk of ischemic cardiomyopathy: history of ischemic heart disease or coronaropathy or/and significant ischemic ECG alterations at screening visit Any clinically significant alterations in the following biological parameters glycemia, kalemia, creatinemia and hematology in the month prior to inclusion according to local laboratory threshold (cf protocol page 33) Vulnerable persons defined in Articles L1121-5 to L 1121-8-1 and L1122-1-2 of the Code de la Santé Publique* (*CSP) Participation in another interventional trial up to 3 months before inclusion Patients having any relevant concomitant disease considered at risk of interfering with study procedures in the opinion of the investigator
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Giorgia Querin, MD
Phone
01 42 16 58 70
Ext
+33
Email
g.querin@institut-myologie.org
First Name & Middle Initial & Last Name or Official Title & Degree
Pierre-Francois Pradat, MD
Phone
01 42 16 24 71
Ext
+33
Email
pierre-francois.pradat@aphp.fr
Facility Information:
Facility Name
Hôpital Pitié Salpêtrière
City
Paris
ZIP/Postal Code
75013
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Giorgia Querin, MD
Phone
01 42 16 58 70
Ext
+33
Email
g.querin@institut-myologie.org

12. IPD Sharing Statement

Plan to Share IPD
No

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Effect of Salbutamol on Walking Capacity in Ambulatory ALS Patients

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